This study is designed to establish a chronic regimen of mini-dose anti-progestin that permits continued menstrual cyclicity, but alters gonadal and/or reproductive tract function to achieve contraceptive activity. Artificial menstrual cycles were established in 3 ovariectomized rhesus monkeys with sequential implants of estradiol (E; 3 weeks) followed by E plus progesterone (P). One week after E + P, animals received the anti-progestin ZK 137 316 (ZK; Schering AG) at 0.03 mg/kg and 0.1 mg/kg (IM, sid for 4 days) in 3 successive treatment cycles to determine the highest dose that would permit cyclicity. Menses was consistently induced with 0.1 mg within 24 hr of the last injection but not with 0.03 mg. To confirm these results during the midluteal phase of a normal menstrual cycle, 0.03 and 0.1 mg/kg ZK (n=3/group) were administered (IM, sid) for 3 days. Premature menses was observed in 2/3 animals within 48 hr of the last 0.1 mg injection, but in 0/3 monkeys receiving 0.03 mg. Daily blood samples were obtained from 27 rhesus monkeys throughout normal menstrual cycles to establish typical levels of E, P and luteinizing hormone (LH) as well as lengths of the follicular and luteal phases. Beginning at menses of the next cycle, animals were assigned to receive vehicle (controls; n=6), 0.01 (n=8), 0.03 (n=8) or 0.1 mg/kg (n=5) ZK (IM, sid) for 4 consecutive cycles. During the first treatment cycle, ovulatory stigma were observed 2-3 days post-LH surge in all groups. Relative to controls, there were no differences in follicular and luteal phase lengths as well as E and P levels with 0.01 and 0.03 mg; however, 3/5 animals receiving 0.1 mg displayed either premature menses or inadequate luteal phase P patterns. Endometrial histology of uterine biopsies obtained at midluteal phase is currently being evaluated. Treatments are continuing to establish the chronic dose of anti-progestin that allows continued menstrual cyclicity.